Synaptic Ca2+-activated K+ channels, SK2 channels, influence neurotransmission, synaptic plasticity, and learning and memory. Blocking SK channel activity facilitates synaptic plasticity and learning and memory while overexpressing SK2 or pharmacologically increasing SK channel activity impairs these processes. We discovered the molecular and cellular mechanisms that are likely responsible for the effects of SK2 channels on synaptic plasticity, the leading model for cellular changes underlying learning and memory. We showed that the activity of SK2 channels in the dendritic spines of hippocampal CA1 pyramidal neurons is coupled to NMDAR activity. Synaptically evoked Ca2+ entry into spines activates synaptic SK2 channels that repolarize the spine membrane potential, thereby favoring Mg2+ re-block of NMDARs, and thus limiting Ca2+ influx through NMDARs that is crucial to the induction of synaptic plasticity. In addition we showed that plasticity-dependent trafficking of SK2 channels itself contributes to the expression of NMDAR-dependent long-term potentiation. New results suggest that SK2 channel trafficking is linked to NMDAR trafficking that is orchestrated and coordinated by a novel family of synaptic scaffolding proteins to affect synaptic dynamics. We will use an integrated repertoire of electrophysiology in fresh brain slice preparations and recordings from transfected cells, biochemical pull-down assays and reconstitutions experiments, and innovative immuno-electron microscopy to examine the molecular and cellular mechanisms that engender the orchestrated trafficking of SK2 channels and NMDARs. The results have profound implications for novel interventional strategies to treat a wide range of cognitive disorders. PUBLIC HEALTH RELEVANCE: Long-term synaptic plasticity is widely thought to be the cellular substrate for learning and memory. The proposed research will illuminate novel pathways and molecules employed by neurons in the brain to orchestrate cellular rearrangements that engender synaptic plasticity. Therefore, this work will reveal potential therapeutic targets for a wide range of cognitive and other brain disorders.